Telomeres are nucleoprotein complexes at the ends of eukaryotic chromosomes that are required for chromosomal integrity. Several hundred nucleotides of telomere repeats cap each chromosomal end, and in the absence of telomerase activity, telomeres shorten with each cell division (1). Eventually, uncapped telomeres trigger cell death or senescence. Cancer cells seem to divide ad infinitum and therefore, require some telomere maintenance mechanism to avoid this fate. Because telomerase activity is generally higher in cancer cells than normal cells, it was originally believed that telomerase was somehow activated in cancer cells (2-6). However, it was subsequently realized that telomerase was only inactive in terminally differentiated cells and that normal stem cells in self-renewing tissues retained telomerase activity (1, 7-9). Because normal stem cells must replicate throughout the long lifetimes of mammals (which can be more than a century in humans), it is clear that such cells must also retain telomerase activity. Because normal stem cells are thought to be the progenitors of cancers, there would be no need to specifically activate telomerase in cancer cells; the enzyme was already active in the precursors, just as were the hundreds of other enzymes and proteins normally required for cell proliferation.
This view was challenged by the discovery of another mechanism for maintaining telomere length i.e., alternative lengthening of telomeres (ALT) (10-12). ALT occurs in the absence of telomerase activity and seems to be dependent on homologous recombination. It occurs in a particularly high fraction of certain tumor types, such as sarcomas, pancreatic neuroendocrine tumors, and brain tumors, but rarely in most common tumor types, such as those tumor types of the colon, breast, lung, prostate, or pancreas (13). Why would cancer cells need ALT if telomerase activity was already constitutively active in their precursors? This question was highlighted by the discovery that many ALT cancers harbor mutations in alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX), genes encoding proteins that interact with each other at telomeres (10, 11). Presumably, the absence of functional ATRX/DAXX complexes permits the homologous recombination resulting in ALT. At minimum, these data were compatible with the ideas that there could be a selective advantage for genetic alterations that results in telomere maintenance and that telomerase is not indefinitely activated in all normal stem cell precursors of cancers.
Another challenge to the idea that genetic alterations were not required for telomerase activation in cancer was raised by the finding that mutations of the telomerase reverse transcriptase (TERT) promoter occurred in ˜70% of melanomas and in a small number of tumor cell lines derived from various tissue types (14, 15). Importantly, only 5 of 110 cell lines derived from lung, stomach, ovary, uterus, or prostate cancers harbored TERT promoter mutations, whereas 19 mutations were found among 37 cell lines derived from various other tumor types. This situation is analogous to the situation for ALT, which is infrequently observed in common epithelial cancers but is observed more regularly in tumors derived from nonepithelial cells, particularly sarcomas and brain tumors (13).
There is a continuing need in the art for biomarkers that help detect, monitor, and characterize tumors, as well as that help predict the effects of tumors on patients.